Is EPX p.Arg645Gln (c.1934G>A) pathogenic?

EPX p.Arg645Gln (c.1934G>A) is classified Uncertain significance in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: ambiguous (0.4299); Ultra-rare (popmax 0.0481%, nfe).

How common is EPX p.Arg645Gln (c.1934G>A) in the general population?

EPX p.Arg645Gln (c.1934G>A) is ultra-rare (popmax 0.0481%, nfe) (gnomAD).

What do computational predictors say about EPX p.Arg645Gln (c.1934G>A)?

AlphaMissense predicts ambiguous (score 0.4299) — an in-silico prediction, not a clinical call.

EPX p.Arg645Gln

c.1934G>A · rs141104307 · VCV2590620

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4299 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0481%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4299	ambiguous
REVEL	0.596	indeterminate
SaProt	LLR -12.34	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.44 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0481% European (non-Finnish) · 566/1,177,720 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0434%

Overall 0.0374% 603/1,611,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0481%	2,081
Remaining individualsnot grpmax-eligible	0.0224%	4,458
Middle Eastern	0.0165%	6,054
African / African-American	0.0133%	7,498
Finnishnot grpmax-eligible	0.00625%	16,003
South Asian	0.00549%	18,208
Admixed American	0.00333%	30,015
East Asian	0.00223%	44,870

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPX
Protein: p.Arg645Gln
Coding: c.1934G>A
MANE Select: NM_000502
dbSNP: rs141104307
Type: single nucleotide variant
Location: chr17:58203306 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.40 · 1 PDB
Residue 645: an α-helix

Full EPX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPX p.Arg645Pro Uncertain significance ★ ⚠ same residue
EPX c.170+5A>G Likely benign ★★ same type
EPX c.464+8C>T Benign ★★ same type
EPX c.801+1G>A Likely benign ★★ same type
EPX p.Asn572Tyr Benign ★★ same type
EPX p.Cys257Ter Benign ★★ same type
EPX p.Leu624= Benign/Likely benign ★★ same type
EPX p.Phe308Leu Likely benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/epx-p-arg645gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown